ClinVar Miner

Submissions for variant NM_000834.4(GRIN2B):c.3047G>A (p.Arg1016Lys) (rs141109968)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000718620 SCV000849484 uncertain significance History of neurodevelopmental disorder 2017-05-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
CeGaT Praxis fuer Humangenetik Tuebingen RCV000416110 SCV000493646 uncertain significance not provided 2016-09-30 criteria provided, single submitter clinical testing
GeneDx RCV000416110 SCV000241299 uncertain significance not provided 2016-07-26 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the GRIN2B gene. The R1016K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved in mammals. However, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with GRIN2B-related disorders (Stenson et al., 2014). Additionally, the R1016K variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000555205 SCV000659529 uncertain significance Mental retardation, autosomal dominant 6; Epileptic encephalopathy, early infantile, 27 2017-07-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 1016 of the GRIN2B protein (p.Arg1016Lys). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and lysine. This variant is present in population databases (rs141109968, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with GRIN2B-related disease. ClinVar contains an entry for this variant (Variation ID: 205715). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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